Annexin A6 mediates calcium-dependent exosome secretion during plasma membrane repair

  1. Justin Krish Williams
  2. Jordan Matthew Ngo
  3. Isabelle Madeline Lehman
  4. Randy Schekman  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Howard Hughes Medical Institute, University of California, Berkeley, United States

Abstract

Exosomes are an extracellular vesicle (EV) subtype that is secreted upon fusion of multivesicular bodies (MVBs) with the plasma membrane. Exosomes may participate in intercellular communication and have utility as disease biomarkers; however, little is known regarding the physiological stimuli that induce their secretion. Ca2+ influx promotes exosome secretion, raising the possibility that exosomes are secreted during the Ca2+-dependent plasma membrane repair of tissues damaged by mechanical stress in vivo. To determine whether exosomes are secreted upon plasma membrane damage, we developed sensitive assays to measure exosome secretion in intact and permeabilized cells. Our results suggest that exosome secretion is coupled to Ca2+-dependent plasma membrane repair. We find that annexin A6 (ANXA6), a well-known plasma membrane repair protein, is recruited to MVBs in the presence of Ca2+ and required for Ca2+-dependent exosome secretion, both in intact and in permeabilized cells. ANXA6 depletion stalls MVBs at the cell periphery, and ANXA6 truncations localize to different membranes, suggesting that ANXA6 may serve to tether MVBs to the plasma membrane. We find that cells secrete exosomes and other EVs upon plasma membrane damage and propose that repair-induced secretion may contribute to the pool of EVs present within biological fluids.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting source data files. Source Data files have been provided for Figure 2, Figure 2 - Figure supplement 1, Figure 3, Figure 4, and Figure 4 - Figure supplement 1. Video Files have been provided for Figure 6 - Videos 1- 6.

Article and author information

Author details

  1. Justin Krish Williams

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Jordan Matthew Ngo

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  3. Isabelle Madeline Lehman

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  4. Randy Schekman

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    For correspondence
    schekman@berkeley.edu
    Competing interests
    Randy Schekman, Founding Editor-in-Chief, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8615-6409

Funding

Howard Hughes Medical Institute

  • Randy Schekman

Sergey Brin Family Foundation (N/A)

  • Randy Schekman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University, United States

Publication history

  1. Received: January 31, 2023
  2. Accepted: May 18, 2023
  3. Accepted Manuscript published: May 19, 2023 (version 1)

Copyright

© 2023, Williams et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Justin Krish Williams
  2. Jordan Matthew Ngo
  3. Isabelle Madeline Lehman
  4. Randy Schekman
(2023)
Annexin A6 mediates calcium-dependent exosome secretion during plasma membrane repair
eLife 12:e86556.
https://doi.org/10.7554/eLife.86556

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